15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a key prostaglandin catabolic enzyme catalyzing the oxidation and inactivation of prostaglandin E(2) (PGE(2)) synthesized from the cyclooxygenase (COX) pathway. Accumulating evidence indicates that 15-PGDH may function as a tumor suppressor antagonizing the action of COX-2 oncogene. 15-PGDH has been found to be down-regulated contributing to elevated levels of PGE(2) in most tumors. The expression of 15-PGDH and COX-2 appears to be regulated reciprocally in cancer cells. Down-regulation of 15-PGDH in tumors is due, in part, to transcriptional repression and epigenetic silencing. Numerous agents have been found to up-regulate 15-PGDH by down-regulation of transcriptional repressors and by attenuation of the turnover of the enzyme. Up-regulation of 15-PGDH may provide a viable approach to cancer chemoprevention. Further catabolism of 15-keto-prostaglandin E(2) is catalyzed by 15-keto-prostaglandin-∆(13)-reductase (13-PGR), which also exhibits LTB(4)-12-hydroxydehydrogenase (LTB(4)-12-DH) activity. 13-PGR/LTB(4)-12-DH behaves as a tumor suppressor as well. This review summarizes current knowledge of the expression and function of 15-PGDH and 13-PGR/LTB(4)-12-DH in lung and other tissues during tumor progression. Future directions of research on these prostaglandin catabolic enzymes as tumor suppressors are also discussed.